Editorial

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Open AccessEditorial

Special Issue “Sympathetic Nerves and Cardiovascular Diseases”

by Yutang Wang and Kate M. Denton

Int. J. Mol. Sci. 2024, 25(5), 2633; https://doi.org/10.3390/ijms25052633 - 23 Feb 2024

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Cardiovascular diseases (CVDs) constitute a spectrum of disorders affecting the heart and blood vessels, which include coronary heart disease, cerebrovascular disease, and peripheral artery disease [...] Full article

(This article belongs to the Special Issue Sympathetic Nerves and Cardiovascular Diseases)

Research

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15 pages, 3512 KiB

Open AccessArticle

Moxonidine Increases Uptake of Oxidised Low-Density Lipoprotein in Cultured Vascular Smooth Muscle Cells and Inhibits Atherosclerosis in Apolipoprotein E-Deficient Mice

by Yutang Wang, Dinh Tam Nguyen, Jack Anesi, Ahmed Alramahi, Paul K. Witting, Zhonglin Chai, Abdul Waheed Khan, Jason Kelly, Kate M. Denton and Jonathan Golledge

Int. J. Mol. Sci. 2023, 24(4), 3857; https://doi.org/10.3390/ijms24043857 - 14 Feb 2023

Cited by 5 | Viewed by 2346

Abstract

This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect [...] Read more.

This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE^−/−) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE^−/− mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE^−/− mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma. Full article

(This article belongs to the Special Issue Sympathetic Nerves and Cardiovascular Diseases)

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12 pages, 1141 KiB

Open AccessArticle

The Effect of Renal Denervation on T Cells in Patients with Resistant Hypertension

by Marta Kantauskaite, Oliver Vonend, Mina Yakoub, Philipp Heilmann, Andras Maifeld, Peter Minko, Lars Schimmöller, Gerald Antoch, Dominik N. Müller, Claudia Schmidt, Blanka Duvnjak, Ulf Zierhut, Sebastian A. Potthoff, Lars C. Rump, Johannes C. Fischer and Johannes Stegbauer

Int. J. Mol. Sci. 2023, 24(3), 2493; https://doi.org/10.3390/ijms24032493 - 27 Jan 2023

Cited by 3 | Viewed by 1430

Abstract

(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN [...] Read more.

(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) Methods: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) Results: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (T_EM), CD4+ effector memory residential (T_EMRA) and CD8+ central memory (T_CM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by −17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ T_EM (r −0.421, p = 0.02) and CD8+ T_CM (r −0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ T_EMRA frequencies with increased cellular cytokine production. (4) Conclusions: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN. Full article

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10 pages, 1366 KiB

Open AccessArticle

Acute Severe Heart Failure Reduces Heart Rate Variability: An Experimental Study in a Porcine Model

by Jan Naar, Mikulas Mlcek, Andreas Kruger, Dagmar Vondrakova, Marek Janotka, Michaela Popkova, Otomar Kittnar, Petr Neuzil and Petr Ostadal

Int. J. Mol. Sci. 2023, 24(1), 493; https://doi.org/10.3390/ijms24010493 - 28 Dec 2022

Cited by 1 | Viewed by 1698

Abstract

There are substantial differences in autonomic nervous system activation among heart (cardiac) failure (CF) patients. The effect of acute CF on autonomic function has not been well explored. The aim of our study was to assess the effect of experimental acute CF on [...] Read more.

There are substantial differences in autonomic nervous system activation among heart (cardiac) failure (CF) patients. The effect of acute CF on autonomic function has not been well explored. The aim of our study was to assess the effect of experimental acute CF on heart rate variability (HRV). Twenty-four female pigs with a mean body weight of 45 kg were used. Acute severe CF was induced by global myocardial hypoxia. In each subject, two 5-min electrocardiogram segments were analyzed and compared: before the induction of myocardial hypoxia and >60 min after the development of severe CF. HRV was assessed by time-domain, frequency-domain and nonlinear analytic methods. The induction of acute CF led to a significant decrease in cardiac output, left ventricular ejection fraction and an increase in heart rate. The development of acute CF was associated with a significant reduction in the standard deviation of intervals between normal beats (50.8 [20.5–88.1] ms versus 5.9 [2.4–11.7] ms, p < 0.001). Uniform HRV reduction was also observed in other time-domain and major nonlinear analytic methods. Similarly, frequency-domain HRV parameters were significantly changed. Acute severe CF induced by global myocardial hypoxia is associated with a significant reduction in HRV. Full article

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13 pages, 1954 KiB

Open AccessArticle

Relative Contribution of Blood Pressure and Renal Sympathetic Nerve Activity to Proximal Tubular Sodium Reabsorption via NHE3 Activity

by Roberto B. Pontes, Erika E. Nishi, Renato O. Crajoinas, Maycon I. O. Milanez, Adriana C. C. Girardi, Ruy R Campos and Cassia T Bergamaschi

Int. J. Mol. Sci. 2023, 24(1), 349; https://doi.org/10.3390/ijms24010349 - 26 Dec 2022

Cited by 1 | Viewed by 2704

Abstract

We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve [...] Read more.

We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve stimulation (RNS) on the renal excretion of sodium and water and its effect on sodium-hydrogen exchanger 3 (NHE3) activity. Uninephrectomized anesthetized male Wistar rats were divided into three groups: (1) Sham; (2) Bic PVN: (3) RNS + Bic injection into the PVN. BP and rSNA were recorded, and urine was collected prior and after the interventions in all groups. RNS decreased sodium (58%) and water excretion (53%) independently of BP changes (p < 0.05). However, after Bic injection in the PVN during RNS stimulation, the BP and rSNA increased by 30% and 60% (p < 0.05), respectively, diuresis (5-fold) and natriuresis (2.3-fold) were increased (p < 0.05), and NHE3 activity was significantly reduced, independently of glomerular filtration rate changes. Thus, an acute increase in the BP overcomes RNS, leading to diuresis, natriuresis, and NHE3 activity inhibition. Full article

(This article belongs to the Special Issue Sympathetic Nerves and Cardiovascular Diseases)

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14 pages, 2886 KiB

Open AccessArticle

Asprosin in the Paraventricular Nucleus Induces Sympathetic Activation and Pressor Responses via cAMP-Dependent ROS Production

by Xiao-Li Wang, Jing-Xiao Wang, Jun-Liu Chen, Wen-Yuan Hao, Wen-Zhou Xu, Zhi-Qin Xu, Yu-Tong Jiang, Pei-Qi Luo, Qi Chen, Yue-Hua Li, Guo-Qing Zhu and Xiu-Zhen Li

Int. J. Mol. Sci. 2022, 23(20), 12595; https://doi.org/10.3390/ijms232012595 - 20 Oct 2022

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Abstract

Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This [...] Read more.

Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This study was designed to determine the roles and underlying mechanisms of asprosin in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male adult SD rats under anesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded, and PVN microinjections were performed bilaterally. Asprosin mRNA and protein expressions were high in the PVN. The high asprosin expression in the PVN was involved in both the parvocellular and magnocellular regions according to immunohistochemical analysis. Microinjection of asprosin into the PVN produced dose-related increases in RSNA, MAP, and HR, which were abolished by superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), and NADPH oxidase inhibitor apocynin. The asprosin promoted superoxide production and increased NADPH oxidase activity in the PVN. Furthermore, it increased the cAMP level, adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in the PVN. The roles of asprosin in increasing RSNA, MAP, and HR were prevented by pretreatment with AC inhibitor SQ22536 or PKA inhibitor H89 in the PVN. Microinjection of cAMP analog db-cAMP into the PVN played similar roles with asprosin in increasing the RSNA, MAP, and HR, but failed to further augment the effects of asprosin. Pretreatment with PVN microinjection of SQ22536 or H89 abolished the roles of asprosin in increasing superoxide production and NADPH oxidase activity in the PVN. These results indicated that asprosin in the PVN increased the sympathetic outflow, blood pressure, and heart rate via cAMP–PKA signaling-mediated NADPH oxidase activation and the subsequent superoxide production. Full article

(This article belongs to the Special Issue Sympathetic Nerves and Cardiovascular Diseases)

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11 pages, 1921 KiB

Open AccessArticle

Aerobic Exercise Prevents Arterial Stiffness and Attenuates Hyperexcitation of Sympathetic Nerves in Perivascular Adipose Tissue of Mice after Transverse Aortic Constriction

by Niujin Shi, Jingbo Xia, Chaoge Wang, Jie Zhou, Junhao Huang, Min Hu and Jingwen Liao

Int. J. Mol. Sci. 2022, 23(19), 11189; https://doi.org/10.3390/ijms231911189 - 23 Sep 2022

Cited by 2 | Viewed by 1878

Abstract

We aimed to investigate the efficacy of exercise on preventing arterial stiffness and the potential role of sympathetic nerves within perivascular adipose tissue (PVAT) in pressure-overload-induced heart failure (HF) mice. Eight-week-old male mice were subjected to sham operation (SHAM), transverse aortic constriction-sedentary (TAC-SE), [...] Read more.

We aimed to investigate the efficacy of exercise on preventing arterial stiffness and the potential role of sympathetic nerves within perivascular adipose tissue (PVAT) in pressure-overload-induced heart failure (HF) mice. Eight-week-old male mice were subjected to sham operation (SHAM), transverse aortic constriction-sedentary (TAC-SE), and transverse aortic constriction-exercise (TAC-EX) groups. Six weeks of aerobic exercise training was performed using a treadmill. Arterial stiffness was determined by measuring the elastic modulus. The elastic and collagen fibers of the aorta and sympathetic nerve distribution in PVAT were observed. Circulating noradrenaline (NE), expressions of β3-adrenergic receptor (β3-AR), and adiponectin in PVAT were quantified. During the recovery of cardiac function by aerobic exercise, thoracic aortic collagen elastic modulus (CEM) and collagen fibers were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX), and elastin elastic modulus (EEM) was significantly increased (p < 0.05, TAC-SE vs. TAC-EX). Circulating NE and sympathetic nerve distribution in PVAT were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX). The expression of β3-AR was significantly reduced (p < 0.05, TAC-SE vs. TAC-EX), and adiponectin was significantly increased (p < 0.05, TAC-SE vs. TAC-EX) in PVAT. Regular aerobic exercise can effectively prevent arterial stiffness and extracellular matrix (ECM) remodeling in the developmental course of HF, during which sympathetic innervation and adiponectin within PVAT might be strongly implicated. Full article

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Review

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Open AccessReview

Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity

by Christian A. Reynolds and Zeljka Minic

Int. J. Mol. Sci. 2023, 24(6), 5378; https://doi.org/10.3390/ijms24065378 - 11 Mar 2023

Cited by 8 | Viewed by 3423

Abstract

Chronic pain affects many people world-wide, and this number is continuously increasing. There is a clear link between chronic pain and the development of cardiovascular disease through activation of the sympathetic nervous system. The purpose of this review is to provide evidence from [...] Read more.

Chronic pain affects many people world-wide, and this number is continuously increasing. There is a clear link between chronic pain and the development of cardiovascular disease through activation of the sympathetic nervous system. The purpose of this review is to provide evidence from the literature that highlights the direct relationship between sympathetic nervous system dysfunction and chronic pain. We hypothesize that maladaptive changes within a common neural network regulating the sympathetic nervous system and pain perception contribute to sympathetic overactivation and cardiovascular disease in the setting of chronic pain. We review clinical evidence and highlight the basic neurocircuitry linking the sympathetic and nociceptive networks and the overlap between the neural networks controlling the two. Full article

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23 pages, 1100 KiB

Open AccessReview

Leptin Increases: Physiological Roles in the Control of Sympathetic Nerve Activity, Energy Balance, and the Hypothalamic–Pituitary–Thyroid Axis

by Davide Martelli and Virginia L. Brooks

Int. J. Mol. Sci. 2023, 24(3), 2684; https://doi.org/10.3390/ijms24032684 - 31 Jan 2023

Cited by 9 | Viewed by 3273

Abstract

It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin [...] Read more.

It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin in the hypothalamus, most notably on arcuate nucleus (ArcN) orexigenic neuropeptide Y neurons and anorexic pro-opiomelanocortin neurons. However, the question addressed in this review is whether the effects of increased leptin levels are also significant on the long-term control of energy balance, despite conventional wisdom to the contrary. We focus on leptin’s actions (in both lean and obese individuals) to decrease food intake, increase sympathetic nerve activity, and support the hypothalamic–pituitary–thyroid axis, with particular attention to sex differences. We also elaborate on obesity-induced inflammation and its role in the altered actions of leptin during obesity. Full article

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20 pages, 1016 KiB

Open AccessReview

Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin

by Evgenii Ivanov, Marina Akhmetshina, Aleksei Erdiakov and Svetlana Gavrilova

Int. J. Mol. Sci. 2023, 24(3), 2045; https://doi.org/10.3390/ijms24032045 - 20 Jan 2023

Cited by 8 | Viewed by 3563

Abstract

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both [...] Read more.

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research. Full article

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18 pages, 1254 KiB

Open AccessReview

Stellate Ganglia and Cardiac Sympathetic Overactivation in Heart Failure

by Yu-Long Li

Int. J. Mol. Sci. 2022, 23(21), 13311; https://doi.org/10.3390/ijms232113311 - 01 Nov 2022

Cited by 9 | Viewed by 4878

Abstract

Heart failure (HF) is a major public health problem worldwide, especially coronary heart disease (myocardial infarction)-induced HF with reduced ejection fraction (HFrEF), which accounts for over 50% of all HF cases. An estimated 6 million American adults have HF. As a major feature [...] Read more.

Heart failure (HF) is a major public health problem worldwide, especially coronary heart disease (myocardial infarction)-induced HF with reduced ejection fraction (HFrEF), which accounts for over 50% of all HF cases. An estimated 6 million American adults have HF. As a major feature of HF, cardiac sympathetic overactivation triggers arrhythmias and sudden cardiac death, which accounts for nearly 50–60% of mortality in HF patients. Regulation of cardiac sympathetic activation is highly integrated by the regulatory circuitry at multiple levels, including afferent, central, and efferent components of the sympathetic nervous system. Much evidence, from other investigators and us, has confirmed the afferent and central neural mechanisms causing sympathoexcitation in HF. The stellate ganglion is a peripheral sympathetic ganglion formed by the fusion of the 7th cervical and 1st thoracic sympathetic ganglion. As the efferent component of the sympathetic nervous system, cardiac postganglionic sympathetic neurons located in stellate ganglia provide local neural coordination independent of higher brain centers. Structural and functional impairments of cardiac postganglionic sympathetic neurons can be involved in cardiac sympathetic overactivation in HF because normally, many effects of the cardiac sympathetic nervous system on cardiac function are mediated via neurotransmitters (e.g., norepinephrine) released from cardiac postganglionic sympathetic neurons innervating the heart. This review provides an overview of cardiac sympathetic remodeling in stellate ganglia and potential mechanisms and the role of cardiac sympathetic remodeling in cardiac sympathetic overactivation and arrhythmias in HF. Targeting cardiac sympathetic remodeling in stellate ganglia could be a therapeutic strategy against malignant cardiac arrhythmias in HF. Full article

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27 pages, 2449 KiB

Open AccessReview

Sympathetic Nerve Activity and Blood Pressure Response to Exercise in Peripheral Artery Disease: From Molecular Mechanisms, Human Studies, to Intervention Strategy Development

by Lu Qin, Jian Cui and Jianhua Li

Int. J. Mol. Sci. 2022, 23(18), 10622; https://doi.org/10.3390/ijms231810622 - 13 Sep 2022

Cited by 3 | Viewed by 2067

Abstract

Sympathetic nerve activity (SNA) regulates the contraction of vascular smooth muscle and leads to a change in arterial blood pressure (BP). It was observed that SNA, vascular contractility, and BP are heightened in patients with peripheral artery disease (PAD) during exercise. The exercise [...] Read more.

Sympathetic nerve activity (SNA) regulates the contraction of vascular smooth muscle and leads to a change in arterial blood pressure (BP). It was observed that SNA, vascular contractility, and BP are heightened in patients with peripheral artery disease (PAD) during exercise. The exercise pressor reflex (EPR), a neural mechanism responsible for BP response to activation of muscle afferent nerve, is a determinant of the exaggerated exercise-induced BP rise in PAD. Based on recent results obtained from a series of studies in PAD patients and a rat model of PAD, this review will shed light on SNA-driven BP response and the underlying mechanisms by which receptors and molecular mediators in muscle afferent nerves mediate the abnormalities in autonomic activities of PAD. Intervention strategies, particularly non-pharmacological strategies, improving the deleterious exercise-induced SNA and BP in PAD, and enhancing tolerance and performance during exercise will also be discussed. Full article

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